紫杉醇
微管蛋白
紫杉烷
癌症研究
癌症
药理学
黑色素瘤
转移
作用机理
多重耐药
流出
癌细胞
微管
抗药性
生物
医学
体外
内科学
生物化学
细胞生物学
乳腺癌
微生物学
作者
Kinsie E. Arnst,Yuxi Wang,Dong-Jin Hwang,Yi Xue,Terry Costello,D. R. Hamilton,Qiang Chen,Jinliang Yang,Frank Park,James T. Dalton,Duane D. Miller,Wei Li
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2018-01-01
卷期号:78 (1): 265-277
被引量:90
标识
DOI:10.1158/0008-5472.can-17-0577
摘要
Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small-molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8Å. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7-10 nmol/L. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation, and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy.Significance: These findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation antitubulin drug for cancer therapy. Cancer Res; 78(1); 265-77. ©2017 AACR.
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